1
Titles and legends to supplementary tables and figures:
Table S1a: BDI for rs7757037, rs4713899, rs9368881, and rs1360780 by abuse
Table S1b: Numbers for rs7757037, rs4713899, rs9368881, and rs1360780 by abuse
Table S2: Estimated means (95% CI) of BDI-II values across groups of the putative interaction between rs1360780 and physical
Table S3a: Estimated means (95% CI) of BDI-II values across groups of the putative interaction between rs1360780 and the five CTQ dimensions
Table S3b: Numbers for the corresponding Table S3a
Table S4. Overall severe abuse
Table S5: Pairwise correlation coefficients between the five CTQ dimensions.
Table S6: Covariate values, observed outcome MDD, estimated logistic probability (π) of MDD, and the value of the four diagnostic statistics ∆β,
∆X², ∆D, and leverage (h) for the four most extreme covariate patterns.
Table S7: Estimated coefficients from all data and when the covariate patterns of each of the subjects (1-4) with the most extreme covariate patterns
are deleted.
Figure S1: LD plot based on n=4081 subjects from SHIP-0 (Haploview 4.1). Four SNPs from the Affymetrix Human SNP Array 6.0 met the
following criteria: Call rate > 95%, HWE >0.01 and MAF> 0.1. The linkage disequilibrium (LD) among the SNPs is depicted as r-squared with
complete LD =1 (black) and no LD =0 (white).
Figure S2: Physical Position of rs7757037, rs4713899, re1360780 and rs9368881 on the FKBP5 gene based on HapMap Data Rel 28 Phase II+III,
August 10, on NCBI B36 assembly. The FKBP5 gene spans 115.3 kbp on chromosome 6, position 35,649,346 bis 35,764,692.
Figure S3: The MDS components were calculated using PLINK and the results were plotted in R. SNPs were used as basis for generating the
multidimensional scaling (MDS) plot that were available in both the HapMap III r3 dataset and in the imputed dataset of the SHIP cohort (described
2
in the Methods section), fulfilling the following QC criteria: HWE test p-value > 10-6, SNP call rate > 95%, minor allele frequency > 1%. Finally,
494,375 SNPs went into the analysis.
ASW : African ancestry in Southwest USA CEU : Utah residents with Northern and Western European ancestry from the CEPH collection CHB :
Han Chinese in Beijing, China CHD : Chinese in Metropolitan Denver, Colorado GIH : Gujarati Indians in Houston, Texas JPT : Japanese in
Tokyo, Japan LWK : Luhya in Webuye, Kenya MEX : Mexican ancestry in Los Angeles, California MKK : Maasai in Kinyawa, Kenya TSI :
Tuscan in Italy YRI : Yoruban in Ibadan, Nigeria (West Africa) SHIP: SHIP-LEGEND sample, northeast of Germany
Figure S4: The positive and negative predictive values of the TT genotype are based on a sensitivity=22.2% and specificity =95.7% (reflecting our
values: 6/(6+21) and 67/(67+3) in subjects with physical abuse) for the MDD endpoint. Note that the positive and negative predictive values apply
for subjects with childhood physical abuse only.
3
Table S1a: BDI for rs7757037, rs4713899, rs9368881, and rs1360780 by abuse (if not stated otherwise then none/mild versus
moderate/severe)
* p<0.05, note: rs4713899 has a cell number of only 1 in the last column.
None/mild
Abuse
SNP
Moderate/severe
0
1
2
0
1
2
rs7757037
rs4713899
rs1360780
rs9368881
GG
GG
CC
GG
AG
AG
CT
AG
AA
AA
TT
AA
GG
GG
CC
GG
AG
AG
CT
AG
AA
AA
TT
AA
Physical
abuse
rs7757037
rs4713899
rs1360780
rs9368881
4.6 (3.9 – 5.3)
5.1 (4.6 – 5.5)
5.2 (4.7 – 5.7)
5.2 (4.7 – 5.8)
5.1 (4.6 – 5.7)
5.0 (4.3 – 5.7)
5.0 (4.4 – 5.5)
4.9 (4.3 – 5.4)
5.4 (4.6 – 6.2)
4.4 (1.7 – 7.1)
4.3 (3.0 – 5.7)
4.9 (3.8 – 6.1)
10.6 (7.1 – 14.2)
9.4 (7.4 – 11.5)
10.3 (7.8 – 12.7)
11.4 (8.8 – 13.9)
10.1 (7.9 – 12.4)
12.9 (9.9 – 16.0)
9.6 (7.2 – 12.1)
8.7 (6.3 – 11.1)
12.4 (8.8 – 16.0)
15.5 (6.1 – 25.0)
17.4 (12.0 – 22.9) *
16.8 (11.7 – 22.0)
Emotional abuse
rs7757037
rs4713899
rs1360780
rs9368881
4.6 (3.9 – 5.3)
5.0 (4.5 – 5.4)
5.1 (4.6 – 5.6)
5.1 (4.6 – 5.7)
5.0 (4.5 – 5.5)
5.1 (4.4 – 5.8)
4.9 (4.4 – 5.5)
4.8 (4.3 – 5.4)
5.4 (4.6 – 6.2)
4.4 (1.7 – 7.1)
4.4 (3.1 – 5.7)
5.0 (3.9 – 6.2)
13.0 (8.6 – 17.3)
13.7 (11.5 – 15.8)
14.4 (11.9 – 17.0)
14.3 (11.7 – 16.8)
14.0 (11.5 – 16.5)
14.0 (10.0 – 18.0)
12.5 (9.4 – 15.5)
12.7 (9.6 – 15.7)
14.5 (10.9 – 18.1)
31.2 (15.1 – 47.4) *
17.3 (11.1 – 23.4)
17.3 (11.1 – 23.4)
Sexual
abuse
rs7757037
rs4713899
rs1360780
rs9368881
4.7 (4.0 – 5.5)
5.2 (4.7 – 5.6)
5.3 (4.7 – 5.8)
5.3 (4.8 – 5.9)
5.2 (4.7 – 5.8)
5.2 (4.4 – 5.9)
5.1 (4.5 – 5.7)
5.0 (4.4 – 5.5)
5.5 (4.7 – 6.3)
4.5 (1.8 – 7.2)
4.6 (3.3 – 6.0)
5.2 (4.0 – 6.4)
5.9 (2.0 – 9.9)
7.5 (5.2 – 9.9)
8.8 (6.1 – 11.5)
8.8 (6.0 – 11.6)
8.7 (5.9 – 11.6)
9.3 (5.9 – 12.7)
6.9 (3.8 – 10.1)
7.0 (4.0 – 10.1)
9.7 (6.3 – 13.1)
18.2 (6.6 – 29.9)
10.6 (5.6 – 15.7)
10.7 (5.6 – 15.7)
Overall:
none/mild versus
moderate/severe
abuse
rs7757037
rs4713899
rs1360780
rs9368881
4.5 (3.8 – 5.3)
4.9 (4.4 – 5.3)
5.0 (4.4 – 5.6)
5.0 (4.4 – 5.6)
4.9 (4.4 – 5.4)
4.8 (4.1 – 5.5)
4.8 (4.2 – 5.4)
4.7 (4.2 – 5.3)
5.2 (4.4 – 6.0)
4.1 (1.3 – 7.0)
4.3 (3.0 – 5.7)
4.9 (3.7 – 6.1)
8.2 (5.7 – 10.7)
9.0 (7.5 – 10.4)
9.7 (8.0 – 11.5)
10.3 (8.5 – 12.1)
9.5 (7.8 – 11.1)
10.2 (8.0 – 12.5)
8.7 (6.9 – 10.5)
8.1 (6.3 – 9.9)
10.5 (8.0 – 12.9)
13.0 (4.8 – 21.1)
11.3 (7.1 – 15.4)
11.3 (7.3 – 15.3)
none/mild/moderate
Overall:
none/mild/moderate
versus severe abuse
rs7757037
rs4713899
rs1360780
rs9368881
4.6 (3.9 – 5.3)
5.0 (4.5 – 5.4)
5.2 (4.6 – 5.7)
5.2 (4.7 – 5.8)
5.1 (4.6 – 5.6)
5.2 (4.5 – 5.9)
5.0 (4.4 – 5.6)
4.9 (4.3 – 5.4)
severe
5.5 (4.7 – 6.3)
4.4 (1.6 – 7.1)
4.4 (3.1 – 5.7)
5.0 (3.8 – 6.2)
13.9 (9.4 – 18.5)
12.4 (10.2 – 14.6)
12.2 (9.5 – 14.9)
12.0 (9.3 – 14.7)
10.7 (8.2 – 13.2)
9.3 (5.4 – 13.2)
9.9 (7.0 – 12.9)
10.2 (7.3 – 13.1)
13.3 (9.3 – 17.3)
31.0 (14.6 – 47.3) *
20.2 (13.5 – 26.8) *
20.2 (13.5 – 26.8) *
4
Table S1b: Numbers for rs7757037, rs4713899, rs9368881, and rs1360780 by abuse adjusted for sex, age and number of adult traumata.
none
factor
mild
moderate
severe
0
1
2
0
1
2
0
1
2
0
1
2
rs7757037
rs4713899
rs1360780
rs9368881
GG
GG
CC
GG
AG
AG
CT
AG
AA
AA
TT
AA
GG
GG
CC
GG
AG
AG
CT
AG
AA
AA
TT
AA
GG
GG
CC
GG
AG
AG
CT
AG
AA
AA
TT
AA
GG
GG
CC
GG
AG
AG
CT
AG
AA
AA
TT
AA
Physical
abuse
rs7757037
rs4713899
rs1360780
rs9368881
559
1399
943
847
960
519
855
905
423
38
158
203
19
65
43
39
54
26
42
46
17
0
6
6
14
34
22
20
30
19
29
30
10
2
4
5
7
31
21
21
24
10
16
16
11
1
5
5
Emotional abuse
rs7757037
rs4713899
rs1360780
rs9368881
533
1351
915
821
929
503
821
871
414
36
154
197
49
118
71
64
92
52
93
97
29
2
8
11
5
29
22
22
25
11
15
15
10
0
3
3
9
30
19
19
17
5
13
13
10
1
4
4
Sexual
abuse
rs7757037
rs4713899
rs1360780
rs9368881
557
1429
950
850
1000
521
881
202
416
39
158
202
19
47
39
40
35
26
30
29
19
0
4
4
15
43
30
28
22
13
20
22
20
1
7
7
4
9
8
8
13
11
9
9
4
1
4
4
Overall:
none/mild versus
moderate/severe
abuse
rs7757037
rs4713899
rs1360780
rs9368881
543
1377
922
827
955
514
850
901
413
35
154
197
44
135
93
88
101
53
83
87
46
4
16
17
573
1456
978
879
1011
548
900
954
442
38
164
208
13
55
37
36
44
18
31
32
17
1
6
6
Overall:
rs7757037
none/mild/moderate rs4713899
versus severe abuse rs1360780
rs9368881
5
Table S2: Estimated means (95% CI) of BDI-II values across groups of the putative interaction between rs1360780 and physical abuse 1.)
without considering PTSD, 2.) adjusting for PTSD and 3.) excluding cases with PTSD.
Environment
factor
Environment factor absent;
CT or CC
Environment factor
absent;
TT
Environment factor
present;
CT or CC
Environment factor
present;
TT
n
BDI-II*
n
BDI-II*
n
BDI-II*
n
BDI-II*
1. Adjusted for
age, gender and
number of
traumata
1881
5.1 (4.7 – 5.5)
164
4.3 (3.0 – 5.7)
88
10.0 (8.2 – 11.7)
9
17.4 (12.0 – 22.9)
2. Adjusted for
age, gender,
number of
traumata and
PTSD
1881
Interaction effect/
P value
8.2 (2.3 – 14.1)#
0.006
5.1 (4.8 – 5.5)
4.5 (3.2 – 5.8)
88
9.3 (7.6 – 11.1)
9
15.4 (9.9 – 20.8)
6.7 (0.9 – 12.5)§
0.024
3. Restricted to no
1863
5.0 (4.6 – 5.4)
164
4.4 (3.1 – 5.7)
PTSD
*Estimated means (95% CI)
#
Interaction effect for the first row: 17.4 – 10.0 – (4.3 – 5.1) = 8.2 (95% CI)
§
Interaction effect for the second row: 15.4 – 9.3 – (4.5 – 5.1) = 6.7 (95% CI)
$
Interaction effect for the third row: 17.0 – 9.4 – (4.4 – 5.0) = 8.3 (95% CI)
81
9.4 (7.6 – 11.1)
7
17.0 (11.0 – 23.0)
8.3 (1.9 – 14.7)$
0.011
164
6
Table S3a: Estimated means (95% CI) of BDI-II values across groups of the putative interaction between rs1360780 and the five CTQ
dimensions adjusted for age (restricted cubic splines), sex, and number of adult traumata. Mild, moderate and severe abuse or neglect
groups are compared each to none (reference category).
factor
none
(reference for the related
interaction test)
CT or CC
TT
mild
CT or CC
moderate
TT
CT or CC
related
interaction test
severe
TT
CT or CC
related interaction
test
Global
test for
interaction
TT
P value
related interaction
test
Physical
abuse
5.0 (4.6 – 5.4)
4.4 (3.1 – 5.7)
6.9 (5.1 – 8.7)
2.8 (-4.1 – 9.8)
P=0.355
9.7 (7.3 – 12.0)
19.0 (10.8 – 27.1)
P=0.023
10.4 (7.8 – 13.1)
16.2 (8.9 – 23.5)
P=0.112
0.036
Emotional
abuse
4.7 (4.3 – 5.1)
4.3 (2.9 – 5.6)
8.5 (7.2 – 9.7)
7.3 (1.6 – 12.9)
P=0.806
11.2 (8.5 – 13.9)
7.2 (-2.3 – 16.7)
P=0.484
16.5 (13.7 – 19.3)
24.7 (16.7 – 32.7)
P=0.048
0.208
Sexual
abuse
5.1 (4.7 – 5.5)
4.5 (3.2 – 5.9)
7.7 (5.7 – 9.7)
9.7 (1.5 – 17.9)
P=0.547
7.2 (4.8 – 9.5)
2.8 (-3.6 – 9.3)
P=0.297
10.6 (6.6 – 14.6)
23.6 (15.4 – 31.8)
P=0.004
0.019
Physical
neglect
4.0 (3.5 – 4.5)
3.7 (2.0 – 5.3)
6.7 (5.9 – 7.4)
5.5 (2.5 – 8.5)
P=0.634
8.5 (7.4 – 9.6)
8.2 (5.2 – 12.3)
P=0.988
7.9 (6.1 – 9.6)
11.5 (4.1 – 18.8)
P=0.324
0.725
Emotional
neglect
4.0 (3.5 – 4.4)
4.0 (2.4 – 5.7)
6.5 (5.8 – 7.2)
6.3 (3.8 – 8.7)
P=0.824
8.7 (7.1 – 10.3)
0.6 (-5.2 – 6.4)
P=0.011
10.3 (8.8 – 11.7)
11.0 (6.1 – 15.8)
P=0.816
0.080
7
Table S3b: Numbers for the corresponding Table S3a
factor
none
mild
moderate
severe
CT or CC
TT
CT or CC
TT
CT or CC
TT
CT or CC
TT
Physical
abuse
1798
158
85
6
51
4
37
5
Emotional
abuse
1736
154
164
8
37
3
32
4
Sexual
abuse
1831
158
69
4
50
7
17
4
Physical
neglect
1193
105
447
31
223
29
86
5
Emotional
neglect
1203
105
505
43
107
10
129
11
8
Table S4. Overall severe abuse; adjusted for age (restricted cubic splines), sex, and number of adult traumata
factor
abuse
none or mild or moderate
severe
Test for
interaction
CT or CC
TT
CT or CC
TT
n=1878
n=164
n=68
N=6
P value
5.1 (4.7 – 5.5)
4.4 (3.1 – 5.7)
11.2 (9.1 – 13.2)
20.2 (13.5 – 26.8)
0.007
9
Table S5: Pairwise correlation coefficients between the five CTQ dimensions.
Physical abuse
Emotional abuse
Sexual abuse
Physical neglect
Emotional neglect
Physical abuse
1
0.42
0.13
0.23
0.35
Emotional abuse
0.56
1
0.21
0.23
0.39
Italic: four levels of severity
Standard: dichotomous (none to mild versus moderate to severe)
Sexual abuse
0.20
0.30
1
0.06
0.11
Physical neglect
0.28
0.29
0.11
1
0.40
Emotional neglect
0.41
0.46
0.13
0.54
1
10
Table S6: Covariate values, observed outcome MDD, estimated logistic probability (π) of MDD, and the value of the four diagnostic
statistics ∆β, ∆X², ∆D, and leverage (h) for the four most extreme covariate patterns.
subject
age
female
TT
1
2
3
4
52.5
79.0
50.6
85.1
0
0
1
0
1
0
1
1
Physical
abuse
1
0
1
0
Number of
traumata
0
1
1
4
MDD
π
h
∆X²
∆D
∆β
0
1
0
1
0.45
0.03
0.75
0.07
0.139
0.002
0.103
0.014
0.9
29.0
3.4
13.7
1.4
6.8
3.1
5.4
0.151
0.070
0.387
0.191
11
Table S7: Estimated coefficients from all data and when the covariate patterns of each of the subjects (1-4) with the most extreme covariate
patterns are deleted.
variable
Intercept
Age, 1st parameter of the RCS
Age, 2nd parameter of the RCS
Age, 3rd parameter of the RCS
Age, 4th parameter of the RCS
Female
Number of traumata
TT
Physical abuse
TT*Physical abuse
RERI
90% CI
95% CI
RCS: restricted cubic spline
All data
-2.566
0.008
-0.063
0.215
-0.645
0.806
0.494
0.042
0.292
1.768
6.80
0.99 – 26.3
0.46 – 33.7
1
-2.557
0.008
-0.059
0.199
-0.617
0.801
0.492
0.042
0.292
2.066
9.64
1.34 – 42.9
0.68 – 56.3
2
-2.600
0.009
-0.068
0.241
-0.712
0.815
0.501
0.046
0.292
1.766
6.81
0.99 – 26.4
0.46 – 33.8
Covariate pattern deleted
3
4
-2.593
-2.606
0.008
0.009
-0.063
-0.075
0.209
0.276
-0.629
-0.788
0.812
0.812
0.496
0.493
0.042
0.0002
0.291
0.290
2.262
1.809
12.02
6.83
1.91 – 53.0
1.03 – 26.3
1.12 – 69.7
0.51 – 33.6
All four
-2.660
0.010
-0.077
0.278
-0.809
0.821
0.499
0.004
0.290
2.878
22.51
2.52 – 146.0
1.38 – 207.5
12
Supplementary Methods
The modified bootstrap approach was performed using the packages “glmnet”1 and “boot” 2 of the free ware R, version 2.11.1.3 In more detail: For bootstrap samples with
numeric problems a nonparametric bootstrap with constrained maximum likelihood estimate via regularized logistic regression was performed by following function:
reri<-function(datsam,i){
daten<-datsam[i,]
x<- cbind(daten[,1], daten[,2], daten[,3], daten[,4], daten[,5] , daten[,6] , daten[,7] , daten[,9], daten[,10])
y<-daten[,8]+1
fitlr<-glm(y-1~x[,1]+x[,2]+x[,3]+x[,4]+x[,5] +x[,6] +x[,7] +x[,8]+x[,9],family="binomial")
norml1<-abs(fitlr$coef[6])+abs(fitlr$coef[7])+abs(fitlr$coef[8])
if (is.na(norml1)==TRUE | norml1>=10)
{fitlr2= glmnet(x,y,family="binomial", alpha=1)
forRERI<-coef(fitlr2,s=0.01)
return(exp(forRERI[6]+forRERI[7]+forRERI[8])-exp(forRERI[6])-exp(forRERI[7])+1)}
else return(exp(fitlr$coef[6]+fitlr$coef[7]+fitlr$coef[8])-exp(fitlr$coef[6])-exp(fitlr$coef[7])+1)
}
Different constraints were set for “norml1”: In the range from 6 to 13 the results were stable with regard to standard errors and biases of bootstrapping. A constraint greater than
14 was not appropriate because this resulted in large standard errors and biases. A constraint smaller than 6 yielded standard errors and biases that were too small.
References:
1.
2.
3.
Friedman J, Hastie T, Tibshirani R (2010). Regularization Paths for Generalized Linear Models via Coordinate Descent. Journal of Statistical Software, 33(1), 1-22.
URL http://www.jstatsoft.org/v33/i01/.
Canty A and Ripley B (2010). boot: Bootstrap R (S-Plus) Functions. R package version 1.2-42.
R Development Core Team (2010). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-90005107-0, URL http://www.R-project.org.